Central nervous system (CNS) disorders are extremely challenging to treat because invasive procedures risk damaging healthy nervous tissue and systemically administered drug therapies often fail due to the barriers of the CNS. The Blood-Brain Barrier (BBB) and Blood-Spinal Cord Barrier (BSCB) regulate the specialized environment of the CNS and prevent foreign molecules from reaching their target. One method to circumvent these barriers is through the use of ultrasound, which can facilitate drug delivery by temporarily opening the barrier between the blood vessels and the brain or spinal cord. This effect can be directed to specific sites without impacting the surrounding tissue. Although ultrasound-mediated drug delivery has been extensively studied in the brain and has reached clinical investigations, limited work has been done to further this technology for the spinal cord despite an urgent need for novel therapies for spinal cord disorders. One condition where there is the potential to have significant impact is in the treatment of leptomeningeal metastatic disease. Leptomeningeal metastases (LM) are a serious complication of cancer and are diagnosed in approximately 5% of patients with solid tumors. LM occurs when cancer spreads and infiltrates the lining of brain and spinal cord, causing neurological symptoms. Incidence rates are increasing, as both control of systemic disease and diagnostic methods are improving. There are no effective treatments for LM, and the spinal cord is more restricted than the brain with respect to currently available therapies. Our goal in this grant is to establish the feasibility of ultrasound-mediated drug delivery as a treatment for LM in the spinal cord. To accomplish this we will: First, determine optimal sonication parameters that maximize drug delivery to the spinal cord and use these parameters to perform a survival study in a rat model of spinal cord LM. Second, demonstrate that low-frequency ultrasound can be directed non-invasively through the intact spinal column at clinically-relevant scale (porcine model) to induce BSCB opening, and test the safety of repeat treatments with respect to motor function. Because there is significant potential for ultrasound-mediated drug delivery to impact patient outcome in LM by delivering existing therapeutics, it is an excellent disease target around which to develop this technology for the spinal cord. More broadly, this work will lay the foundation to extend ultrasound- mediated drug delivery to the spinal cord to other conditions including Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy and spinal cord injury, with the potential for broad patient impact.